Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. adults currently smoking. Though there are medications approved by the FDA to treat nicotine addiction, they are minimally effective and at least 80% of those seeking treatment relapse within one year. Rewarding aspects of nicotine as well as aversive properties, such as those associated with abstinence, may act synergistically to direct the behavior of smokers toward tobacco consumption. Symptoms associated with nicotine withdrawal include increased anxiety and cognitive deficits. To date, few studies have investigated the molecular and cellular changes that occur during chronic exposure to nicotine and how these molecules are altered during withdrawal. Previously, we and others have established that the transcription factor CREB is a central mediator of addictive behaviors. We now made the discovery that one of the targets of CREB in the brain is the LKB1/AMPK pathway. AMP-activated kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that has a major role in the periphery in sensing cellular energy status and regulating fuel availability. Its role in the brain is virtually unknown. Preliminary data indicates that the AMPK pathway and its downstream targets are misregulated during nicotine exposure and withdrawal. The proposed mechanistic and translational studies will determine the functional role of this protein on nicotine reward behavior and withdrawal symptoms and will afford the development of novel or repurposed pharmacological treatments designed to promote smoking cessation.